RESEARCH - Vioxx (rofecoxib) doses >25 mg/day triple risk of acute MI and sudden cardiac death

[Guest guest]

Rofecoxib doses >25 mg/day triple risk of acute MI and sudden cardiac

death

Rheumawire

Aug 26, 2004

Janis

Bordeaux, France - A late-breaking presentation by Dr J Graham (US

Food and Drug Administration Office of Drug Safety) at an international

pharmacoepidemiology meeting included startling data showing that

high-dose rofecoxib (Vioxx, Merck & Co) triples the risk of heart attack

and sudden cardiac death compared with the risk in patients not taking

coxibs or other nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. The

study, which was funded by the US Food and Drug Administration (FDA),

also found that patients taking rofecoxib at more typical doses of <25

mg/day had a 50% greater risk of heart attack and sudden cardiac death

than patients taking any dose of celecoxib (Celebrex, Pfizer).

" Rofecoxib use at a dose >25 mg/day increases the risk of acute

myocardial infarction (AMI) and sudden cardiac death (SCD). This and

other studies cast serious doubt on the safety of rofecoxib >25 mg/day

and its use by physicians and patients, " Graham said. " For patients

treated with a COX-2 selective NSAID, rofecoxib <25 mg/day conferred an

increased risk of AMI and SCD compared with celecoxib. From a

cardiovascular perspective, celecoxib may be safer than rofecoxib.

Additional research comparing rofecoxib with celecoxib is needed, but

the cardiovascular safety of other coxibs should not be assumed. "

This study was undertaken an attempt to sort out suggestions from

several previous studies, including a randomized clinical trial, that

higher-dose rofecoxib increases the risk of AMI. An additional goal was

to resolve conflicting data on possibly decreased AMI risk associated

with naproxen use. Graham pointed out that a methodological concern was

that many of the previous studies did not include sudden cardiac death

(SCD) as an outcome.

The study objectives were to determine whether celecoxib, ibuprofen,

naproxen, rofecoxib, or other NSAID use increases the risk of AMI and

SCD and to determine whether the risk is similar among COX-2 selective

agents.

These questions were approached by analyzing the medical records of 1.4

million people insured by the Kaiser Permanente health maintenance

organization and treated with a COX-2 selective or nonselective NSAID

between January 1, 1999 and December 31, 2001. Patients were entered

into the study cohort beginning with their first prescription and

followed until the end of the study period, disenrollment, AMI, or

death.

The study population included 40 405 patients treated with celecoxib and

26 748 treated with rofecoxib. The most commonly used other NSAIDs were

ibuprofen (991 261), naproxen (435 492), indomethacin (118 261),

nabumetone (93 976), and sulindac (78 481).

A nested case-control study was done within this NSAID-exposed study

cohort. Study outcomes were AMI requiring hospitalization (from computer

files) or out-of-hospital SCD (from death certificate data). Cases were

all NSAID-exposed cohort members with AMI or SCD during the study

period. Controls were risk-set matched Kaiser members matched 4:1 on

event (index) date, birth year, gender, and health-plan region.

NSAID exposure was rated current if use overlapped index date, recent if

use ended from 1to 60 days before the index date, or remote if use ended

more than 60 days before index date. The comparison of interest was

current vs remote exposure.

A cardiovascular risk score (CVRS) with 10 values (0 to 9) was created

because of the high number of covariates. " There was a 12-fold

difference in AMI/SCD risk between the lowest and highest score, " Graham

said.

" The main findings were that higher-dose rofecoxib (>25 mg/day)

conferred a 3.15-fold increased risk of AMI and SCD compared with remote

use of any NSAID. Risk was also increased with lower-dose rofecoxib (<25

mg/day) but not significantly so, compared with remote NSAID use. Risk

of AMI and SCD was increased with lower-dose rofecoxib compared with

celecoxib (p=0.04). Naproxen use did not confer a protective effect;

rather it increased risk by 18% (p=0.01), " Graham reported. The analysis

also showed that indomethacin and possibly diclofenac increased the risk

of AMI and SCD.

Although rofecoxib is approved at doses up to 50 mg for the treatment of

acute pain for periods of not more than 5 days, the researchers found

that many patients continued far beyond that time.

Graham also pointed out that the 95% CI for rofecoxib <25 mg/day

excluded the point estimate for celecoxib risk and vice versa. " The risk

of AMI/ SCD was increased in patients taking lower-dose rofecoxib

compared with celecoxib (Wald test: p=0.04), " he said.

Blake, a Merck spokesperson, told the Wall Street Journal

that the company " disagrees with the conclusion " of the latest study and

that randomized, controlled trials have shown no significant differences

between in the rate of serious cardiovascular events in patients taking

rofecoxib vs placebo [2]. Rofecoxib is a $2.5 billion-a-year product for

the company.

Sources

Graham DJ, Campen DH, Cheetham C, et al. Risk of

acute cardiac events among patients treated with cyclooxygenase-2

selective and nonselective nonsteroidal antiinflammatory drugs. 20th

International Conference on Pharmacoepidemiology & Therapeutic Risk

Management; August 22-25, 2004; Bordeaux, France. Poster 59.

Mathews AW and Hensley S. Big HMO reconsiders Vioxx

after study points to heart risks. Wall Street Journal. August 26,

2004; Available at: http://www.wsj.com

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org